title: Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.
abstract: Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of µ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits NaV1.7 with an IC50 of ∼25 nM. µ-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, for which the selectivity is 32-fold. µ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. µ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemical-induced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes µ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting NaV1.7, which might be suitable for treating a wide range of human pain pathologies.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences and Yunnan Province, Kunming 650223, Yunnan, China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Yang
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiao
authors.forename: Di
authors.initials: D
authors.lastname: Kang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Eivind A B
authors.initials: EA
authors.lastname: Undheim
authors.forename: Julie K
authors.initials: JK
authors.lastname: Klint
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Rong
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001180:Arthropod Venoms / Q000737:chemistry*; D001181:Arthropods / Q000737:chemistry; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D001180:Arthropod Venoms; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010455:Peptides; C486866:SCN9A protein, human; D009020:Morphine
keywords: chronic pain; drug discovery; peptide therapeutic